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PubMedDate not supplied

A case study of the evolving software architecture for the FDA generic drug application process.

This primary goal of this project was to develop a software architecture to support the Food and Drug Administration (FDA) generic drug application process by making it more efficient and effective. The secondary goal was to produce a scalable, modular, and flexible architecture that could be generalized to other contexts in interorganizational health care communications. The system described here shows improvements over the old system for the generic drug application process for most of the defined design objectives. The modular, flexible design that produced this new system offers lessons for the general design of distributed health care information systems and points the way to robust application frameworks that will allow practical development and maintenance of a distributed infrastructure.

Drug Approval↗
PubMed2002

Sleep symptoms and polysomnographic architecture in advanced Parkinson's disease after chronic bilateral subthalamic stimulation.

OBJECTIVE: To evaluate the sleep symptoms and polysomnographic architecture in advanced Parkinson's disease after chronic bilateral subthalamic stimulation (STN-DBS). METHODS: Sleep was studied in 11 patients (six women and five men; mean (SD) age 63.6 (7.8) years) who underwent STN-DBS. Subjective sleep evaluation was assessed by clinical sleep interview and the Pittsburgh sleep quality index (PSQI) questionnaire, and sleep architecture by polysomnography with audiovisual recording. Nocturnal mobility was evaluated. RESULTS: Before surgery, eight patients rated their sleep quality as unsatisfactory; seven of these had a marked improvement after surgery, and the PSQI questionnaire showed significantly improved sleep quality. After surgery, polysomnography showed an increase in the longest period of uninterrupted sleep and a decrease in the arousal index. There was an increase in nocturnal mobility after surgery, but no change in REM sleep behaviour disorder. CONCLUSIONS: In advanced Parkinson's disease, chronic STN-DBS is associated with subjective improvement in sleep quality, probably through increased nocturnal mobility and reduction of sleep fragmentation.

Aged↗
PubMed2001

Design of a neurofuzzy controller with simplified architecture.

This work presents the design of a neurofuzzy controller with simplified architecture that minimizes the processing time used in several stages associated with systems and processes modelling. The basic procedures of fuzzification and defuzzification are very simplified, whereas the inference procedures are computed in a direct way. The simplified architecture has allowed a fast and easy configuration of the neurofuzzy controller, as consequence, the control rules that define the control actions are obtained automatically. To validate the proposed approach, this neurofuzzy system is used in an industrial application for fluid flow control.

Fuzzy Logic↗
PubMed1993

An architecture for fully integrated large scale neural networks.

To apply neural networks to many engineering applications, large networks will be required. Such networks are difficult to build using standard crystalline silicon technology due to limitations in both the fabrication and packaging processes. An architecture is proposed where amorphous silicon photoresistors are used to store the synaptic weights. A single plate of amorphous silicon is able to contain up to 100 million photoresistors, exploiting readily available fabrication technology. Using an external light source, each photoresistor can be individually adjusted allowing them to be configured as programmable fixed-value resistors. The processing compatibility of polysilicon and amorphous silicon allows the same glass substrate to be used for large-area integration of the photosensors, the analogue neural network and the neurons. The integration of the photosensors and the rest of the network may be used to alleviate the interface problem at the inputs resulting in a design with a very simple architecture that is both elegant and simple to fabricate. This paper describes such a design in which amorphous silicon technology is applied to neural network hardware.

Algorithms↗
PubMed1994

Generation of associative processes in a neural network with realistic features of architecture and units.

A recent neural network model of cortical associative memory incorporating neuronal adaptation by a simplified description of its underlying ionic mechanisms is extended towards more realistic network units and architecture. Excitatory units correspond to groups of adapting pyramidal neurons and inhibitory units to groups of nonadapting interneurons. The network architecture is formed from pairs of one pyramidal and one interneuron unit each with inhibitory connections within and excitatory connections between pairs. The degree of adaptability of the pyramidal units controls the character of the network dynamics. An intermediate adaptability generates limit cycles of transitions between stored patterns and regulates oscillation frequencies in the range of theta rhythms observed in the brain. In particular, neuronal adaptation can impose a direction of transitions between overlapping patterns also in a symmetrically connected network. The model permits a detailed analysis of the transition mechanisms. Temporal sequences of patterns thus formed may constitute parts of associative processes, such as recall of stored sequences or search of pattern subspaces. As a special case, neuronal adaptation can accomplish pattern segmentation by which overlapping patterns are temporally resolved. The type of limit cycles produced by neuronal adaptation may also be of significance for central pattern generators, also for networks involving motor neurons. The applied learning rule of Hebbian type is compared to a modified version also common in neural network modelling. It is also shown that the dependence of the network dynamic behaviour on neuronal adaptability, from fixed point attractors at weak adaptability towards more complex dynamics of limit cycles and chaos at strong adaptability, agrees with that recently observed in a more abstract version of the model. The present description of neuronal adaptation is compared to models based on dynamic firing thresholds.

Association↗
PubMed1996

VLSI neural system architecture for finite ring recursive reduction.

The use of neural-like networks to implement finite ring computations has been presented in a previous paper. This paper develops efficient VLSI neural system architecture for the finite ring recursive reduction (FRRR), including module reduction, MSB carry iteration and feedforward processing. These techniques deal with the basic principles involved in constructing a FRRR, and their implementations are efficiently matched to the VLSI medium. Compared with the other structure models for finite ring computation (e.g. modification of binary arithmetic logic and bit-steered ROM's), the FRRR structure has the lowest area complexity in silicon while maintaining a high throughput rate. Examples of several implementations are used to illustrate the effectiveness of the FRRR architecture.

Algorithms↗
PubMed2005

Personality architecture: within-person structures and processes.

This chapter reviews theory and research on intraindividual personality structures and processes. Principles for modeling the architecture of personality, that is, the overall design and operating characteristics of intraindividual personality systems, are addressed. Research demonstrates that a focus on within-person structures and processes advances the understanding of two aspects of personality coherence: the functional relations among distinct elements of personality, and cross-situational coherence in personality functioning that results from interactions among enduring knowledge structures and dynamic appraisal processes. Also reviewed are recent conceptual and empirical advances, which demonstrate that the interindividual personality variables that summarize variability in the population are wholly insufficient for modeling intraindividual personality architecture.

Cognition↗
PubMed1986

Architecture, composition, and contractile properties of rat soleus muscle grafts.

Skeletal muscle grafts have a deficit in tension development compared with control muscles, even after accounting for reduced mass and total muscle cross-sectional area. Our purpose was to determine relationships among the architecture, tissue composition, and contractile properties of rat soleus muscle grafts. Data were compared with control soleus muscles obtained from littermates. Female Wistar rats were anesthetized with pentobarbital sodium for grafting of soleus muscles with nerve implant and for dissection of muscles 56 days after grafting. Compared with control values, the maximum specific tension (N/cm2) of grafts was 76%, the interstitial (inulin) space was 135%, and the connective tissue protein concentration was 177%. For grafts, total muscle length and fiber length were 91 and 123% of control values, respectively. The extrapolated shortening velocity at zero load (fiber lengths/s) for grafts was not different from the control value. The deficit in specific tension of grafts is explained by a greater concentration of noncontractile tissue components. Changes in muscle architecture and composition following grafting had little affect on contraction dynamics.

Animals↗
PubMed1999

Laminar fiber architecture and three-dimensional systolic mechanics in canine ventricular myocardium.

Previous studies suggest that the laminar architecture of left ventricular myocardium may be critical for normal ventricular mechanics. However, systolic three-dimensional deformation of the laminae has never been measured. Therefore, end-systolic finite strains relative to end diastole, from biplane radiography of transmural markers near the apex and base of the anesthetized open-chest canine anterior left ventricular free wall (n = 6), were referred to three-dimensional laminar microstructural axes reconstructed from histology. Whereas fiber shortening was uniform [-0.07 +/- 0.04 (SD)], radial wall thickening increased from base (0. 10 +/- 0.09) to apex (0.14 +/- 0.13). Extension of the laminae transverse to the muscle fibers also increased from base (0.08 +/- 0. 07) to apex (0.11 +/- 0.08), and interlaminar shear changed sign [0. 05 +/- 0.07 (base) and -0.07 +/- 0.09 (apex)], reflecting variations in laminar architecture. Nevertheless, the apex and base were similar in that at each site laminar extension and shear contributed approximately 60 and 40%, respectively, of mean transmural thickening. Kinematic considerations suggest that these dual wall-thickening mechanisms may have distinct ultrastructural origins.

Animals↗
PubMed2001

Inferences on force transmission from muscle fiber architecture of the canine diaphragm.

Functional properties of the diaphragm are mediated by muscle structure. Modeling of force transmission necessitates a precise knowledge of muscle fiber architecture. Because the diaphragm experiences loads both along and transverse to the long axes of its muscle fibers in vivo, the mechanism of force transmission may be more complex than in other skeletal muscles that are loaded uniaxially along the muscle fibers. Using a combination of fiber microdissections and histological and morphological methods, we determined regional muscle fiber architecture and measured the shape of the cell membrane of single fibers isolated from diaphragm muscles from 11 mongrel dogs. We found that muscle fibers were either spanning fibers (SPF), running uninterrupted between central tendon (CT) and chest wall (CW), or were non-spanning fibers (NSF) that ended within the muscle fascicle. NSF accounted for the majority of fibers in the midcostal, dorsal costal, and lateral crural regions but were only 25-41% of fibers in the sternal region. In the midcostal and dorsal costal regions, only approximately 1% of the NSF terminated within the fascicle at both ends; the lateral crural region contained no such fibers. We measured fiber length, tapered length, fiber diameters along fiber length, and the taper angle for 271 fibers. The lateral crural region had the longest mean length of SPF, which is equivalent to the mean muscle length, followed by the costal and sternal regions. For the midcostal and crural regions, the percentage of tapered length of NSF was 45.9 +/- 5.3 and 40.6 +/- 7.5, respectively. The taper angle was approximately 0.15 degrees for both, and, therefore, the shear component of force was approximately 380 times greater than the tensile component. When the diaphragm is submaximally activated, as during normal breathing and maximal inspiratory efforts, muscle forces could be transmitted to the cell membrane and to the extracellular intramuscular connective tissue by shear linkage, presumably via structural transmembrane proteins.

Animals↗
PubMed1984

Muscle architecture and force-velocity relationships in humans.

The in vivo torque-velocity relationships of the knee extensors (KE), knee flexors (KF), ankle plantarflexors (PF), and ankle dorsiflexors (DF) were determined in 12 untrained subjects using an isokinetic testing device (Cybex II). These data were then matched to the predicted maximum forces and shortening velocities derived from muscle architectural determinations made on three hemipelvectomies (36). The torque-velocity curves of all muscle groups resembled that predicted by Hill's (19, 20) equation except at the higher forces and lower velocities. The peak torques occurred at mean velocities ranging from 41-62 rad X s-1 for the KE, KF, and PF. Although the peak torque of the DF occurred at the isometric loading condition, it was also lower than that predicted by Hill's equation. The muscle fiber length and physiological cross-sectional area measurements indicate that the architecture of the human leg musculature has a major influence on the torque-velocity characteristics. These data corroborate previous findings (24) that some neural inhibitory mechanism exists in the control of the leg musculature, which limits the maximum forces that could be produced under optimal stimulating conditions.

Adult↗
PubMed2003

Effect of aging on human muscle architecture.

The effect of aging on human gastrocnemius medialis (GM) muscle architecture was evaluated by comparing morphometric measurements on 14 young (aged 27-42 yr) and on 16 older (aged 70-81 yr) physically active men, matched for height, body mass, and physical activity. GM muscle anatomic cross-sectional area (ACSA) and volume (Vol) were measured by computerized tomography, and GM fascicle length (Lf) and pennation angle (theta) were assessed by ultrasonography. GM physiological cross-sectional area (PCSA) was calculated as the ratio of Vol/Lf. In the elderly, ACSA and Vol were, respectively, 19.1% (P < 0.005) and 25.4% (P < 0.001) smaller than in the young adults. Also, Lf and were found to be smaller in the elderly group by 10.2% (P < 0.01) and 13.2% (P < 0.01), respectively. When the data for the young and elderly adults were pooled together, significantly correlated with ACSA (P < 0.05). Because of the reduced Vol and Lf in the elderly group, the resulting PCSA was found to be 15.2% (P < 0.05) smaller. In conclusion, this study demonstrates that aging significantly affects human skeletal muscle architecture. These structural alterations are expected to have implications for muscle function in old age.

Adult↗
PubMed1996

Electrotonic architecture of hippocampal CA1 pyramidal neurons based on three-dimensional reconstructions.

1. The spread of electrical signals in pyramidal neurons from the CA1 field of rat hippocampus was investigated through multicompartmental modeling based on three-dimensional morphometric reconstructions of four of these cells. These models were used to dissect the electrotonic architecture of these neurons, and to evaluate the equivalent cylinder approach that this laboratory and others have previously applied to them. Robustness of results was verified by the use of wide ranges of values of specific membrane resistance (Rm) and cytoplasmic resistivity. 2. The anatomy exhibited extreme departures from a key assumption of the equivalent cylinder model, the so-called "3/2 power law." 3. The compartmental models showed that the frequency distribution of steady-state electrotonic distances between the soma and the dendritic terminations was multimodal, with a large range and a sizeable coefficient of variation. This violated another central assumption of the equivalent cylinder model, namely, that all terminations are electronically equidistant from the soma. This finding, which was observed both for "centrifugal" (away from the soma) and "centripetal" (toward the soma) spread of electrical signals, indicates that the concept of an equivalent electrotonic length for the whole dendritic tree is not appropriate for these neurons. 4. The multiple peaks in the electrotonic distance distributions, whether for centrifugal or centripetal voltage transfer, were clearly related to the laminar organization of synaptic afferents in the CA1 region. 5. The results in the three preceding paragraphs reveal how little of the electrotonic architecture of these neurons is captured by a simple equivalent cylinder model. The multicompartmental model is more appropriate for exploring synaptic signaling and transient events in CA1 pyramidal neurons. 6. There was significant attenuation of synaptic potential, current, and charge as they spread from the dendritic tree to the soma. Charge suffered the least and voltage suffered the most attenuation. Attenuation depended weakly on Rm and strongly on synaptic location. Delay of time to peak was more distorted for voltage than for current and was more affected by Rm. 7. Adequate space clamp is not possible for most of the synapses on these cells. Application of a somatic voltage clamp had no significant effect on voltage transients in the subsynaptic membrane. 8. The possible existence of steep voltage gradients within the dendritic tree is consistent with the idea that there can be some degree of local processing and that different regions of the neuron may function semiautonomously. These spatial gradients are potentially relevant to synaptic plasticity in the hippocampus, and they also suggest caution in interpreting some neurophysiological results.

Animals↗
PubMed2003

Genetic architecture of fast- and slow-twitch skeletal muscle weight in 200-day-old mice of the C57BL/6J and DBA/2J lineage.

The aim of the study was to explore the genetic architecture influencing weight of fast- and slow-twitch skeletal muscles. The weights of the slow-twitch soleus, the mixed gastrocnemius, the fast-twitch tibialis anterior (TA), and extensor digitorum longus (EDL) muscles were 11-34% greater (P < 0.001) in 200-day-old C57BL/6J (B6) than in DBA/2J (D2) mice. Male muscles were 13-28% larger than female (P < 1 x 10(-5), no strain by sex interaction). The sex-related difference in muscle weight, however, varied significantly among the 23 derivative BXD recombinant inbred (RI) strains (strain by sex interaction for soleus, P < 0.01; TA, P < 1 x 10(-4); EDL, not significant; and gastrocnemius, P < 0.001). Quantitative trait loci (QTL) affecting muscle weight were mapped in an F2 intercross of B6 and D2 mice (B6D2F2) and BXD RIs. A total of 10 autosomal, muscle-specific, but not muscle-type-specific, QTL, explaining a total of 5.4, 7.7, 22.9, and 8.6% of phenotypic variance for soleus, TA, EDL, and gastrocnemius muscles, respectively, were found across chromosomes 1 (Chr 1), 2, 3 (female-specific), 5 (two), 6, 7, 8, and 9 in B6D2F2 mice. The QTL on Chr 8 for EDL and the female-specific QTL on Chr 3 for gastrocnemius muscles were statistically significant, but the remaining QTL were at the suggestive level of statistical significance. Ten QTL on Chr 1, 2, 4, 5, 7, 8, 14, 17 (two), and 19 were identified in BXD RIs. Half of the QTL in BXD RIs had pleiotropic effects and were at the suggestive level of significance (except for the significant QTL for gastrocnemius muscle on Chr 17). The B6D2F2 nominated QTL on Chr 8 for EDL weight was validated in BXD RIs (P < 0.03). Support intervals for the QTL on Chr 1 and 5 overlapped between B6D2F2 and BXD RIs. An epistatic interaction between markers on Chr 1 and 17 affected gastrocnemius weight in BXD RIs. The interaction was not, however, validated in the B6D2F2 population. Our results indicate that the differences in muscle weight in the B6 and D2 segregating populations were the outcome of a polygenic system, with each factor contributing a small amount to the phenotypic variance and the genetic architecture affecting muscle weight was muscle specific, but not muscle-type specific, and in some instances sex specific.

Aging↗
PubMed2005

Dynamic genetic architecture of metabolic syndrome attributes in the rat.

The polydactylous rat strain (PD/Cub) is a highly inbred (F > 90) genetic model of metabolic syndrome. The aim of this study was to analyze the genetic architecture of the metabolic derangements found in the PD/Cub strain and to assess its dynamics in time and in response to diet and medication. We derived a PD/Cub x BN/Cub (Brown Norway) F2 intercross population of 149 male rats and performed metabolic profiling and genotyping and multiple levels of genetic linkage and statistical analyses at five different stages of ontogenesis and after high-sucrose diet feeding and dexamethasone administration challenges. The interval mapping analysis of 83 metabolic and morphometric traits revealed over 50 regions genomewide with significant or suggestive linkage to one or more of the traits in the segregating PD/Cub x BN/Cub population. The multiple interval mapping showed that, in addition to "single" quantitative train loci, there are more than 30 pairs of loci across the whole genome significantly influencing the variation of particular traits in an epistatic fashion. This study represents the first whole genome analysis of metabolic syndrome in the PD/Cub model and reveals several new loci previously not connected to the genetics of insulin resistance and dyslipidemia. In addition, it attempts to present the concept of "dynamic genetic architecture" of metabolic syndrome attributes, evidenced by shifts in the genetic determination of syndrome features during ontogenesis and during adaptation to the dietary and pharmacological influences.

Animals↗
PubMed1997

Microvascular architecture of hepatic metastases in a mouse model.

Development of effective treatment for hepatic metastases can be initiated by a better understanding of tumour vasculature and blood supply. This study was designed to characterise the microvascular architecture of hepatic metastases and observe the source of contributory blood supply from the host. Metastases were induced in mice by an intrasplenic injection of colon carcinoma cells (10(6) cells/ml.) Vascularization of tumours was studied over a three week period by scanning electron microscopy of microvascular corrosion casts. Metastatic liver involvement was observed initially within a week post induction, as areas approximately 100 microns in diameter not perfused by the casting resin. On histology these spaces corresponded to tumour cell aggregates. The following weeks highlighted the angiogenesis phase of these tumours as they received a vascular supply from adjacent hepatic sinusoids. Direct sinusoidal supply of metastases was maintained throughout tumour growth. At the tumour periphery most sinusoids were compressed to form a sheath demarcating the tumour from the hepatic vasculature. No direct supply from the hepatic artery or the portal vein was observed. Dilated vessels termed vascular lakes dominated the complex microvascular architecture of the tumours, most tapering as they traversed towards the periphery. Four vascular branching patterns could be identified as true loops, bifurcations and trifurcations, spirals and capillary networks. The most significant observation in this study was the direct sinusoidal supply of metastases, together with the vascular lakes and the peripheral sinusoidal sheaths of the tumour microculature.

Animals↗
PubMed2000

Caveats: numerical requirements in graph theory based quantitation of tissue architecture.

Graph theory based methods represent one approach to an objective and reproducible structural analysis of tissue architecture. By these methods, neighborhood relations between a number of objects (e.g., cells) are explored and inherent to these methods are therefore certain requirements as to the number of objects to be included in the analysis. However, the question of how many objects are required to achieve reproducible values in repeated computations of proposed structural features, has previously not been adressed specifically. After digitising HE stained slides and storing them as grey level images, cell nuclei were segmented and their geometrical centre of gravity were computed, serving as the basis for construction of the Voronoi diagram (VD) and its subgraphs. Variations in repeated computations of structural features derived from these graphs were related to the number of cell nuclei included in the analysis. We demonstrate a large variation in the values of the structural features from one computation to another in one and the same section when only a limited number of cells (100-500) are included in the analysis. This variation decreased with increasing number of cells analyzed. The exact number of cells required to achieve reproducible values differ significantly between tissues, but not between separate cases of similar lesions. There are no significant differences between normal and malignantly changed tissues in oral mucosa with respect to how many cells must be included. For graph theory based analysis of tissue architecture, care must be taken to include an adequate number of objects; for some of the structural features we have tested, more than 3000 cells.

Biometry↗
PubMed2005

Intratumoral recombinant human interleukin-12 administration in head and neck squamous cell carcinoma patients modifies locoregional lymph node architecture and induces natural killer cell infiltration in the primary tumor.

The objective of this study was to evaluate the histologic and immunohistopathologic effects of intratumorally given recombinant human interleukin-12 on the immune cells in the primary tumors and regional lymph nodes. Ten previously untreated patients with head and neck squamous cell carcinoma (HNSCC) were injected in the primary tumor twice to thrice, once weekly, at two dose levels of 100 or 300 ng/kg, before surgery. These patients were compared with 20 non-IL-12-treated control HNSCC patients. In the primary tumor, the number of CD56+ natural killer (NK) cells was increased in IL-12-treated patients compared with control patients. In some IL-12-treated patients, an impressive peritumoral invasion of CD20+ B cells was noticed. No differences were seen in the CD8+ or CD4+ T lymphocytes. Interestingly, major differences were apparent in the architecture of the enlarged lymph nodes of IL-12-treated patients; in particular, the distribution of B cells differed and fewer primary and secondary follicles with smaller germinal centers were observed. In addition, a decrease of dendritic cell lysosyme-associated membrane glycoprotein-positive cells in the paracortex was noted, resulting in a reduction of paracortical hyperplasia. In the lymph nodes, especially the CD56+ NK cells but also the CD8+ and CD4+ T lymphocytes, produced a high amount of IFN-gamma. Patients, irrespectively of IL-12 treatment, with a high number of CD56+ cells in the primary tumor had a better overall survival than those with a low number. In conclusion, after i.t. IL-12 treatment in HNSCC patients, the largest effect was seen on the NK cells, with a higher number in the primary tumor and a high IFN-gamma mRNA expression in the lymph nodes. Significant effects were noted on B cells, with altered lymph node architecture in every IL-12-treated patient and excessive peritumoral infiltration in some patients.

Adjuvants, Immunologic↗